CN111067887A - Application of leonurine crystal in preparation of anti-oxidation type low-density lipoprotein oxLDL (oxLDL) medicine - Google Patents

Application of leonurine crystal in preparation of anti-oxidation type low-density lipoprotein oxLDL (oxLDL) medicine Download PDF

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CN111067887A
CN111067887A CN201811235586.4A CN201811235586A CN111067887A CN 111067887 A CN111067887 A CN 111067887A CN 201811235586 A CN201811235586 A CN 201811235586A CN 111067887 A CN111067887 A CN 111067887A
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leonurine
oxldl
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朱依谆
朱依纯
刘新华
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Fudan University
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Abstract

The invention belongs to the field of modern pharmacy of traditional Chinese medicines, and relates to a Chinese herbal medicine motherwort extract and application thereof in pharmacy, in particular to application of a medicinal crystal form of leonurine of the Chinese herbal medicine motherwort extract in preparation of a medicine, wherein the leonurine has the English name: leonurine; chemical name: 3, 5-dimethoxy-4-hydroxy-benzoic acid (4-guanidino) -1-butyl ester. The invention prepares the leonurine into 1 medicinal crystal by a specific method, wherein 1 crystal is a hydrate crystal form, and the leonurine has the function of reducing the oxLDL and can be used for treating hyperoxLDL blood disease. The crystal form of the leonurine prepared by the invention can be used for preparing medicines for resisting high oxLDL bloods, preventing endangium injuries and atherosclerosis caused by oxLDL, including medicines for preventing atherosclerosis in specific patients who are easy to develop atherosclerosis because specific LDL is not increased.

Description

Application of leonurine crystal in preparation of anti-oxidation type low-density lipoprotein oxLDL (oxLDL) medicine
Technical Field
The invention belongs to the field of modern pharmacy of traditional Chinese medicines, and relates to application of a crystal of leonurine extracted from Chinese herbal medicine motherwort herb in preparing a medicament, in particular to application in preparing an antioxidant low-density lipoprotein (oxLDL) blood medicament.
Background
The prior art discloses that Low Density Lipoprotein (LDL) is a lipid-protein complex in blood, and is a spherical particle, the inner core of which contains hydrophobic substances such as cholesterol and triglyceride, and the outer shell of which is composed of protein, phospholipid, cholesterol, etc. LDL is an important component in human blood, wherein cholesterol is a structural component of human cell membranes and is necessary for maintaining the normal structure and function of the cell membranes; cholesterol is also a precursor substance necessary for the synthesis of sex hormones and bile acids in the body; triglyceride is an important energy storage substance in the body and participates in normal energy metabolism, so that the industry considers that simply attributing LDL as a source of 'bad cholesterol' harmful to human body is one side, and researches prove that a certain level of LDL in blood is necessary for human health instead.
It has been found through intensive research that oxidized low-density lipoprotein (oxLDL) is clearly responsible for vascular endothelial injury and atherosclerosis. Clinical time observation shows that cases with severe atherosclerosis are not necessarily accompanied by hyperldl syndrome, but often by hyperoxldl syndrome. LDL is not normally oxidized, and it has a strong atherogenic effect only when oxidized to oxLDL in a disease state. In large-scale long-term clinical studies, lipid-lowering therapy mainly based on statins and aiming at lowering LDL is found to substantially fail to finally lower the mortality rate of cardiovascular diseases despite the lowered LDL level, and even increase the mortality rate of patients due to side reactions such as rhabdomyolysis, severe liver damage, glucose metabolism disorder and the like caused by statins; therefore, the results of the research show that the treatment aiming at lowering LDL alone is a misleading area in the current clinical treatment, and does not meet the requirements of modern precise medicine. In fact, the oxLDL is only true "bad cholesterol". Unfortunately, current clinical examinations only measure LDL levels in patients, and not oxLDL, miss large numbers of patients with normal LDL levels, but abnormally elevated oxLDL levels, leaving these patients undetected for long-term exposure to the risk of cardiovascular damage (in fact, research work has found that patients with normal LDL levels and elevated oxLDL levels develop severe vascular endothelial damage and atherosclerosis); therefore, from the perspective of modern precise medicine, patients with clinical dyslipidemia at present need to be more precisely classified, and patients with hyperoxldl disease (LDL may not be increased) are screened for early intervention, so that the patients in the part are prevented from finally suffering from vascular endothelial damage and atherosclerosis. The treatment of high oxLDL blood disease is the accurate medical therapy for preventing and treating cardiovascular diseases such as atherosclerosis.
Motherwort (a plant of the family labiatae, Herba Leonuri, Chinese Motherwort) was originally collected in ancient books such as "shennong's herbal", and "compendium of materia medica", and has the effects of activating blood, regulating menstruation, inducing diuresis and relieving swelling; the pharmacopoeia of the people's republic of China (2000 edition) is used for treating menoxenia, dysmenorrhea, amenorrhea, lochiorrhea, edema oliguria, acute nephritis edema, etc. Earlier researches of the application find that motherwort has a series of new applications except the known functions, including cardiovascular protection effect and the like, and further separate and synthesize a single effective component leonurine, so that a plurality of new applications of leonurine as a candidate drug are determined. The application further analyzes the crystal structure of the leonurine to obtain the optimal medicinal crystal form, and researches show that the leonurine crystal form has the function of resisting oxLDL.
Based on the current state of the art, the inventors of the present application intend to provide a method for treating hyperoxldl blood disease, and particularly relate to the use of leonurine crystals in the preparation of a medicine for resisting hyperoxldl blood disease, wherein the medicine is particularly suitable for early intervention in the formation of atherosclerosis before severe lesions occur, preventing the occurrence of vascular lesions and remarkably reducing the incidence rate of cardiovascular diseases.
Disclosure of Invention
The invention aims to provide a new medicinal application of an active component leonurine crystal of a traditional Chinese medicine motherwort herb in preparing medicines for treating hyperoxLDL blood disease, in particular to an early intervention medicine before oxLDL causes blood vessel damage, which is used for preventing cardiovascular diseases such as atherosclerosis and the like; the leonurine crystals can effectively reduce the level of oxLDL and are used for treating hyperoxLDL syndrome.
It is a further object of the present invention to use the above active ingredients as raw materials for pharmaceutical preparations.
The leonurine is an effective component separated from motherwort and is prepared in large quantities by artificial synthesis, and the chemical structural formula of the leonurine is as follows:
Figure BSA0000172508040000031
the leonurine has the English name: leonurine; chemical name: 3, 5-dimethoxy-4-hydroxy-benzoic acid (4-guanidino) -1-butyl ester.
According to the invention, leonurine can be prepared into 6 crystals with different crystal forms by a specific method, in particular 6 crystals with different structures of leonurine sulfate, wherein 2 are hydrates, 2 are anhydrous crystal forms, one is a methanolate and one is an ethanolate.
For convenience of description, the 6 leonurine crystals described above are respectively named as crystal form a, crystal form B, crystal form C, crystal form D, crystal form E and crystal form F.
The matrine crystal with the resistance to hyperoxLDL blood disease is a crystal form A, and has the following characteristics:
monohydrate crystal form (single crystal structure confirmed), square block crystal. No crystal transformation action is carried out before melting, the crystal form is dehydrated and transformed into an anhydrous crystal form B at the temperature of 120-150 ℃, and the decomposition is started at the temperature of about 250 ℃; in the relative humidity range of 0-95%, the crystal form is not transformed, the hygroscopicity is slightly changed, and no or almost no hygroscopicity is shown; in a suspension experiment at 25 ℃, methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, nitromethane, ethyl acetate, isopropyl acetate, isoamyl alcohol, methyl tert-butyl ether, toluene, methyl isobutyl ketone, n-hexane, n-heptane, diethyl ether, dichloromethane, trichloromethane, petroleum ether, water and other solvents; suspending in 50 deg.C solvent such as methanol, ethanol, acetone, methyl ethyl ketone, isopropyl acetate, methyl tert-butyl ether, toluene, n-hexane, n-heptane, diethyl ether, chloroform, petroleum ether, and water; the crystal form A can be obtained under the condition of most of solvents in suspension and volatilization of mixed solvents at 25 ℃ and 50 ℃.
According to the relationship between the performance and the drug property, the most stable crystal form A in accelerated experiments (40 ℃/75% RH) is preferably the preferable medicinal crystal form of the leonurine sulfate.
The molecular structure of the crystal form A leonurine hemisulfate monohydrate crystal is shown in figure 1;
the leonurine hemisulfate monohydrate crystal represented by the crystal form A is a colorless flaky crystal, belongs to a monoclinic system, has a space group of P-1, and comprises 2 leonurine molecules, 1 sulfate ion and 2 water molecules in an asymmetric unit; wherein the guanidyl of the two leonurine molecules and the negative ions of the sulfate radical form an ionic bond trimer, and the trimer form a two-dimensional structure through the hydrogen bonding action of the guanidyl and the sulfate radical to form a following polymer molecule plane layer (as shown in figure 2);
in the application, the molecular planes of the multilayer polymers of the leonurine hemisulfate monohydrate crystal represented by the crystal form A are arranged in a superposition manner in a parallel mode, the molecular planes with two-dimensional structures form a three-dimensional laminated network structure of the leonurine hemisulfate monohydrate crystal through the hydrogen bonding action of water molecules, and hydrophilic layers formed by guanidino and sulfate radicals and leonurine hydrophobic groups are alternately arranged (as shown in figure 3).
In the present application, the spatial positions of all atoms in the single crystal molecules of the leonurine hemisulfate monohydrate crystal represented by the crystal form a conform to the functional atomic coordinates and the isotropic or equivalent isotropic displacement parameters as shown in table 1 below.
TABLE 1 coordinate and equi-or equi-displacement parameters for all atoms in single crystal molecules of leonurine hemisulfate monohydrate crystals
Figure BSA0000172508040000041
Figure BSA0000172508040000051
Figure BSA0000172508040000061
Figure BSA0000172508040000071
To further characterize the 6 crystal forms of leonurine described above, they were each analyzed by X-ray powder diffraction (XRPD) to provide XRPD data as shown in table 2 below:
table 2 XRPD data for six leonurine crystals:
Figure BSA0000172508040000072
Figure BSA0000172508040000081
Figure BSA0000172508040000091
the 6 leonurine crystal forms are particularly crystals with the XRPD characteristics.
Furthermore, the leonurine crystal can be used for preparing a medicament for treating hyperoxLDL blood disease.
Furthermore, the present invention provides a novel anti-oxLDL drug for further preparing a preventive drug for preventing cardiovascular diseases, which is useful for treating hyperoxLDL blood disease and for blocking early the occurrence of severe angiopathy such as atherosclerosis.
The leonurine crystal is also suitable for being applied to a specific type of patients with lipid metabolism disorder in precise medical practice, namely patients with hyperoxLDL (low blood cholesterol syndrome); in response, a preventive medicine for early blocking before clinical lesion is generated is provided; the medicine can be used for treating diseases secondary to high oxLDL, including but not limited to coronary artery, cerebral artery, carotid artery, femoral artery, etc., and important human blood vessel injury and lesion, especially atherosclerotic lesion.
The leonurine crystal can be used as a medicine raw material, and can be directly prepared into suitable preparations, including capsules, tablets, powder, suspensions and compound preparations, or be mixed with solid or liquid auxiliary materials which are usually used for the preparations in pharmacy.
The invention carries out a large number of pharmacological studies, and results show that the leonurine A-type crystal has the effect of reducing the oxLDL level of high-fat diet animals.
The experiments of the invention were performed with ApoE gene knock-out (ApoE)-/-) Mice are high-fat animal models and are fed with high-fat feed; based on the genetic defect, the leonurine A-type crystal is in a stress state caused by high-fat diet again, and a hyperoxLDL blood disease animal model is successfully created and is used for verifying the treatment effect of the leonurine A-type crystal on the hyperoxLDL blood disease.
The experimental results show that leonurine form A crystals reduce high-fat feeding of ApoE-/-The leonurine crystal can be used for preparing a medicine for treating hyperoxLDL blood disease and further preparing a preventive medicine for preventing cardiovascular diseases, and the medicine is used for treating hyperoxLDL blood disease and can early block the occurrence of severe vascular diseases such as atherosclerosis.
The application provides the application of leonurine crystals in preparing medicines for resisting hyperoxLDL (low-oxygen-content lipoprotein) which are particularly suitable for early intervening in the formation of atherosclerosis before serious lesions occur, preventing the occurrence of vascular lesions and remarkably reducing the incidence rate of cardiovascular diseases, and provides a method for treating hyperoxLDL (low-oxygen-content lipoprotein),
drawings
Figure 1 is the molecular structure of leonurine form a.
Figure 2 is the two-dimensional structure of the leonurine crystalline form a molecule.
Figure 3 is the three-dimensional structure of the leonurine crystalline form a molecule.
FIG. 4 is a graphic representation of leonurine form A crystals for reducing hyperoxLDL hematopathyThe statistical chart of experimental data of the oxLDL level of a model mouse shows that the leonurine A-type crystal can effectively reduce the oxLDL level of a high-oxLDL model mouse. Control, Control group; ApoE-/-,ApoE-/-Knock-out hyperoxldl syndrome model group; ApoE-/-+Leonurine， ApoE-/-The group of leonurine form a crystals was administered to knock-out hyperoxldl leukemia. The average value of the data is +/-standard error, and the sample amount of each group is 1;##P<0.01。
figure 5 is an X-ray powder diffraction pattern of leonurine hemisulfate monohydrate crystals.
Detailed Description
Example 1
High fat animal model experiment verifies that leonurine A type crystal has treatment effect on hyperoxLDL (low-oxygen lipoprotein) blood
The experimental method comprises the following steps: c57BL/6J mice were fed normal diet in SPF-rated animal houses; ApoE knockout mice were fed normally in SPF grade animal houses: adaptively feeding high-fat feed for one week at a ratio of 1: 1, and dividing into the following 3 groups according to a random number table:
control group (C57BL/6J, plain feed, n ═ 10): thirdly, steaming water, and performing intragastric administration once a day;
model set (ApoE)-/-Group, high-fat diet, n ═ 10): thirdly, steaming water, and performing intragastric administration once a day;
leonurine type A crystal group (ApoE)-/-+ leonurine form a crystals, high-fat diet, n ═ 10): gavage at 20 mg/kg/day, once a day;
after the 4-week administration period, mice were anesthetized with pentobarbital sodium according to body weight, blood was taken from the eyeballs, about 0.5 ml of blood was taken from each, centrifuged, and serum was stored at-4 ℃.
Detection indexes are as follows: oxLDL (tokyo bio-technologies ltd);
the detection method comprises the following steps: mouse oxidized low density lipoprotein (OX-LDL) (Nanjing, Biotech, Inc.);
detailed operation procedures are as follows:
a. before use, the kit is balanced at room temperature for half an hour;
b. blank wells: only adding the color developing agents A and B and the stop solution for zero adjustment without adding samples;
c. standard sample wells: diluted standards 50 μ l, zero wells: adding 50 mul of standard substance/sample diluted release solution, and then adding 50 mul of biotin antigen working solution;
d. sample well: adding 50 mul of sample, and then adding 50 mul of biotin antigen working solution;
e. slightly shaking, covering a sealing plate membrane, and incubating in an incubator at 37 ℃ for 30 min;
f. diluting 25 times of the concentrated washing liquid with distilled water for later use;
g. first washing: carefully uncovering the sealing plate film, discarding liquid, spin-drying, filling washing liquid into each hole, standing for 30 seconds, then discarding, repeating the steps for 5 times, and patting dry;
h. adding 50 μ l avidin-HRP into the standard and sample wells, shaking gently, covering with a sealing plate membrane, and incubating in an incubator at 37 deg.C for 30 min;
i. and (3) second washing: carefully uncovering the sealing plate film, discarding liquid, spin-drying, filling washing liquid into each hole, standing for 30 seconds, then discarding, repeating the steps for 5 times, and patting dry;
j. color development: adding 50 mul of color developing agent A into each hole, then adding 50 mul of color developing agent B, lightly shaking and uniformly mixing, and developing for 10 minutes at 37 ℃ in a dark place;
k. and (4) terminating: stop the reaction by adding 50. mu.l of stop solution to each well (blue color immediately turns yellow);
1. and (3) determination: the absorbance (OD value) of each well was measured sequentially at a wavelength of 450nm with the blank well being zeroed. The determination should be performed within 10 minutes after the addition of the stop solution;
m, calculating: calculating a regression equation of a standard curve according to the concentration and the OD value, suggesting to use special calculation software for calculation, recommending to use ELISAcalc for calculation, and selecting a logistic curve (four parameters) as a fitting model;
data were analyzed and plotted using GraphPad Prism statistical software, results were annotated with mean ± standard error (mean ± SEM), data were analyzed with one-way variance (ANOVA), p < 0.05 is a significant difference;
the experimental results are as follows: as shown in fig. 4, ApoE knockout mice developed hyperoxldl disease under high-fat diet conditions, with significantly higher blood oxLDL levels than controls (P < 0.01); the leonurine A crystal can effectively reduce the oxLDL level of a model mouse, and compared with a model group, P of an administration group is less than 0.01.
The experimental results show that leonurine form A crystals reduce high-fat feeding of ApoE-/-The leonurine crystal can be used for preparing a medicine for treating hyperoxLDL blood disease and further preparing a preventive medicine for preventing cardiovascular diseases, and can block the occurrence of severe vascular diseases such as atherosclerosis and the like at an early stage.

Claims (9)

1. Use of leonurine hemisulfate monohydrate crystals of the molecular structure of formula in the manufacture of a medicament for treating hyperoxLDL blood levels, said medicament lowering oxLDL levels in vivo,
Figure FSA0000172508030000011
2. the use according to claim 1, wherein the leonurine hemisulfate monohydrate crystals are colorless plate crystals belonging to monoclinic system, and have space group P-1, and comprise 2 leonurine molecules, 1 sulfate ion and 2 water molecules in an asymmetric unit; wherein, the guanidyl of the two leonurine molecules and the negative ions of the sulfate radical form an ionic bond trimer, and the trimer form a two-dimensional structure through the hydrogen bonding action of the guanidyl and the sulfate radical to form a polymer molecule plane layer; the leonurine crystal which accords with the characteristics is a medicament for treating high oxLDL blood disease and has the pharmacological action of reducing the oxLDL level in vivo;
Figure FSA0000172508030000021
3. the use according to claim 1, characterized in that the planes of the molecules of the multilayer polymer of the crystals of leonurine hemisulfate monohydrate are arranged in a superimposed parallel manner, the planes of the molecules of the two-dimensional structure thereof forming, by hydrogen bonding of water molecules, a three-dimensional layered network of crystals of leonurine hemisulfate monohydrate, the hydrophilic layers of guanidino and sulfate groups thereof forming alternating arrangements with the hydrophobic groups of leonurine; the leonurine crystal which accords with the characteristics is a medicament for treating high oxLDL blood disease and has the pharmacological action of reducing the oxLDL level in vivo;
Figure FSA0000172508030000022
4. the use according to claim 1, characterized in that the leonurine hemisulfate monohydrate crystals have the spatial positions of all atoms in their single crystal molecules in accordance with the following functional atomic coordinates and the parameters of equirectangular or rather equirectangular displacement; the leonurine crystal which accords with the characteristics is a medicament for treating high oxLDL blood disease and has the pharmacological action of reducing the oxLDL level in vivo;
Figure FSA0000172508030000031
Figure FSA0000172508030000041
Figure FSA0000172508030000051
Figure FSA0000172508030000062
。
5. the use as claimed in claim 1, wherein leonurine crystals that conform to the X-ray powder diffraction pattern of the leonurine hemisulfate monohydrate crystals are pharmacological agents for the treatment of hyperoxldl blood disorders, having the pharmacological effect of lowering oxLDL levels in vivo.
6. The use according to claims 1-5, characterized in that the leonurine hemisulfate monohydrate crystals are used for the preparation of a medicament for the prevention of secondary diseases caused by high-oxLDL, such as vascular injury caused by high-oxLDL, and endarterial injury diseases, and for the prevention of endarterial injury of the coronary arteries, cerebral arteries, carotid arteries, and femoral arteries of the heart.
7. Use according to claims 1-5, characterized in that the leonurine hemisulfate monohydrate crystals are used for the preparation of a medicament for the prevention of secondary diseases caused by high-oxLDL, such as atherosclerosis caused by high-oxLDL, and atherosclerosis of the coronary arteries, cerebral arteries, carotid arteries, femoral arteries.
8. Use according to claims 1-5, characterized in that the leonurine hemisulfate monohydrate crystals are used for the preparation of a medicament for the prevention of secondary diseases caused by high-oxLDL, such as atherosclerosis caused by high-oxLDL and atherosclerosis of the coronary arteries, cerebral arteries, carotid arteries, femoral arteries.
9. Use according to claims 1-5, characterized in that the leonurine hemisulfate monohydrate crystals are used for the preparation of a medicament for the prevention of secondary diseases caused by high-oxLDL, such as atherosclerosis caused by high-oxLDL and atherosclerosis prone to development without an increase in specific LDL.
CN201811235586.4A 2018-10-22 2018-10-22 Application of leonurine crystal in preparation of anti-oxidation type low-density lipoprotein oxLDL (oxLDL) medicine Pending CN111067887A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113967205A (en) * 2020-07-22 2022-01-25 复旦大学 Use of Leonurine and its crystals in the preparation of anti-aging medicines

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103565786A (en) * 2012-07-20 2014-02-12 复旦大学 Applications of leonurine in preparation of medicines used for treating atherosclerosis

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
CN103565786A (en) * 2012-07-20 2014-02-12 复旦大学 Applications of leonurine in preparation of medicines used for treating atherosclerosis

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Title
李秀才: "《动脉粥样硬化防治》", 31 July 2018, 中国医药科技出版社 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113967205A (en) * 2020-07-22 2022-01-25 复旦大学 Use of Leonurine and its crystals in the preparation of anti-aging medicines

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Application publication date: 20200428